Severe malarial anemia (SMA) is the primary clinical manifestation of Plasmodium falciparum malaria in African children in holoendemic areas of malaria transmission. Dysregulation in pro- and anti-inflammatory cytokine production is associated with enhanced pathogenesis of SMA in infants and young children. Interleukin (IL)-12 is a pro-inflammatory cytokine associated with protection against childhood SMA. IL-23 is a recently discovered pro-inflammatory cytokine that shares a common p40 subunit with IL-12. Although not investigated in the context of SMA, IL-23 is associated with the pathogenesis of anemia in chronic inflammatory diseases. Moreover, both IL-12 and IL-23 initiate innate immune responses that are down- regulated by IL-10. Both IL-12 and IL-23 have also been reported to be important in the induction of antibody production. Protective innate immune responses occur through IL-18 synergizing with IL-12 to induce interferon (IFN)-gamma production from naive CD4+ T cells, while IL-23 promotes IL-17 production from activated memory CD4+ T cells. The primary goal of this proposal is to investigate the role of the IL-12 and IL-23 cytokine pathways during childhood malarial anemia. This will be accomplished by; 1) determining the association between IL-12 and IL-23 signaling pathways with malarial anemia disease severity; 2) determining the association between IL-12 and IL-23-induced CD4+ T cell responses and malarial anemia disease outcomes; and 3) determining the effect of IL-12 and IL-23 on the in vitro induction of IFN-gamma and IL-17, respectively, and the generation of antibody responses to malaria antigen stimulation. Successful completion of these experimental objectives will provide novel and important information about the role of the IL-12 and IL-23 cytokine pathways in regulating protective clinical immunity in young children naturally exposed to holoendemic P. falciparum malaria transmission. [unreadable] [unreadable] [unreadable]